Osteosarcoma: A multi-institutional study to evaluate an Astra-Zeneca src-kinase inhibitor in pulmonary metastatic osteosarcoma has recently closed. The study was a randomized double blind placebo controlled study. Patients who presented with pulmonary metastases received either complete resection of pulmonary nodules plus treatment with the kinase inhibitor (orally daily) vs. placebo to determine whether DFS could be prolonged with treatment of the src kinase inhibitor. The study was closed after an interim analysis by the DSMB concluded no benefit of the experimental arm. We also completed accrual to the osteosarcoma cohort in a SARC Phase II study using a human monoclonal antibody to the IGFIR in recurrent osteosarcoma. Thirty-five patients from around the U.S. were entered and a manuscript was recently published describing our findings. Ewings Sarcoma: As noted above for the osteosarcoma, we completed an international study using a human monoclonal antibody directed against the IGFI receptor in Ewings rhabdomyosarcoma osteosarcoma synovial sarcoma and several other rare adult type sarcomas through the SARC clinical trials consortium. I served as the chairman of the study committee and played a major role writing the protocol. The study opened in December 2007 and completed accrual in all cohorts including rhabdomyosarcoma, osteosarcoma and Ewings sarcoma. Clear objective responses have been seen in both the Ewings cohort and the rhabdomyosarcoma cohort. We amended the study to treat patients under the age of 18 on a q 3 week schedule at 27 mg/kg and the study was shut down after just 6 patients were entered due to a phase out of the drug by Roche. The overall demonstrated clear activity in Ewings sarcoma, with a relatively low objective response rate of 16.5% but several durable CRs were observed in this refractory population of patients. The data on the Ewings sarcoma cohort was published in 2011. Based upon these findings, the COG is planning to open a Phase III study comparing standard chemotherapy to chemotherapy plus an IGFIR Ab in high risk Ewing's sarcoma patients. We have recently established an international consortium to study PARP inhibitors in Ewings sarcoma based on published work of others and our unpublished data suggesting that Ewings tumors may be particularly sensitivie to PARP inhibition. This Phase I study was recently opened for accrual and we entered the first patient. It is of course too early to comment on the efficacy or toxicity. Pediatric Gastrointestinal Stromal Tumors (GIST): We have continued our program to study pediatric GIST patients, a very rare disease that is biologically distinct from adult GIST patients. Our clinics at NIH bring in patients from across the country as well as physicians with interest/expertise in this rare disease from several centers across the country including surgeons, pediatric and medical oncologists as well as pediatric endocrinologists. Following up on our initial observation of germline mutations in SDH genes in sporadic pediatric GIST patients, we have now shown that the majority of tumors studied to date harbor mutations in one of the SDH A B C or D genes and it appears that at least 50% of these patients harbor germline mutations in these genes. We have also now shown that these SDH mutant GIST tumors also have global hypermethylation in the tumor genome. Based on responses of SDH mutant kidney cancers to VEGFR inhibitors such as vandetanib we very recently opened a clinical study to test this drug in SDH mutant GIST tumors as well. We are also discussing with CTEP the feasibility of testing a demethylating agent in patients with progressive SDH deficient GIST.